Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS

Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an in...

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Bibliographic Details
Published in:The Journal of neuroscience 2012-09, Vol.32 (36), p.12528-12542
Main Authors: Koenning, Matthias, Jackson, Stacey, Hay, Curtis M, Faux, Clare, Kilpatrick, Trevor J, Willingham, Melanie, Emery, Ben
Format: Article
Language:English
Subjects:
Age Factors
Animals
Cell Differentiation - genetics
Central Nervous System - cytology
Central Nervous System - metabolism
Central Nervous System - pathology
Demyelinating Diseases - metabolism
Demyelinating Diseases - pathology
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Myelin Sheath - genetics
Myelin Sheath - metabolism
Myelin Sheath - ultrastructure
Oligodendroglia - cytology
Oligodendroglia - metabolism
Transcription Factors - deficiency
Transcription Factors - genetics
Transcription Factors - physiology
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Summary:Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.1069-12.2012